Initiation of wound healing is regulated by the convergence of mechanical and epigenetic cues

Bhatt, Tanay; Dey, Rakesh; Hegde, Akshay; Ketkar, Alhad Ashok; Pulianmackal, Ajai J.; Deb, Ashim P; Rampalli, Shravanti

doi:10.1371/journal.pbio.3001777

Cited by 8 publications

(5 citation statements)

References 68 publications

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“…Cells were grown to confluency and RNA extracted as described above. For collection of conditioned media from keratinocytes to treat explants, cells were grown in low Calcium E-media as reported previously 58 . Serum free media was added to confluent plates of cells and conditioned media collected after 16 hours.…”

Section: Methodsmentioning

confidence: 99%

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Saha,

Thannimangalath,

Pincha

et al. 2023

Preprint

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Vasculopathy is a common hallmark of various fibrotic disorders including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill-defined. In SSc the vasculopathy typically precedes the onset of fibrosis and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that Angiopoietin-like protein 2 (Angptl2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, Angptl2 upregulates pro-fibrotic genes, downregulates the tight junction protein Claudin 5, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and consequently vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, Angptl2 emerges as a promising early biomarker of the disease and inhibiting the vasculopathy inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to the treatment of fibrotic diseases by targeting the vascular defects.

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Section: Methodsmentioning

confidence: 99%

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Saha,

Thannimangalath,

Pincha

et al. 2023

Preprint

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“…In addition to its role in normal development, DNMT3A positively regulates the expression of genes involved in stem cell proliferation and promotes the expression of genes that drive epidermal differentiation. 46 Bhatt et al 47 demonstrated that after skin injury, cells near the wound edge expressed DNMT3A. Also, the impact of overexpression of DNMT3A has been reported in different cancer cells.…”

Section: Metalloproteinasesmentioning

confidence: 99%

Modulation of gene expression in skin wound healing by photobiomodulation therapy: A systematic review in vivo studies

Pilar,

Brochado,

Schmidt

et al. 2024

Photoderm Photoimm Photomed

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BackgroundWound healing is a multistep process involving coordinated responses of a variety of cell types, cytokines, growth factors, and extracellular matrix (ECM) components leading to the physiological restoration of tissue integrity. Photobiomodulation therapy (PBMT) has been highlighted as an approach to improve the healing process, nonetheless at the molecular level, the effects of PBMT are not entirely understood.AimTo systematically review publications that investigated gene expression after PBMT during in vivo skin repair.MethodsAn electronic search was undertaken in Medline Ovid (Wolters Kluwer), PubMed (National Library of Medicine), Web of Science (Thomson Reuters), Scopus (Elsevier), Embase, and LILACS databases. The search strategy was conducted from the terms: low‐level light therapy, gene expression, and wound healing and their synonyms. The databases were consulted in December 2023 and no publication year limit was used.ResultsEleven studies were included in this review and the expression of 186 genes was evaluated. PBMT modified the expression of several targets genes studied, such as down‐regulation of genes related to extracellular matrix proteases (MMP2 and MMP9) and pro‐inflammatory cytokines (IL10 and IL6) and up‐regulation of DNMT3A and BFGF.ConclusionThis review demonstrates that PBMT is capable of regulating gene expression during wound healing. Most evidence showed a positive impact of PBMT in regulating genes linked to inflammatory cytokines improving skin wound healing. Yet, the effects of PBMT in genes involved in other mechanisms still need to be better understood.

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“…Mechanical stretch on fibroblast promotes hypertrophic scar formation through mechanically activated cation channel Piezo1 and thus therapeutic approaches for scars might target the Piezo1 channel . The tension within the epidermis promotes gene expression through DNA methyltransferase 3A (DNMT3A) nuclear translocation, which is a potential regulator of skin repair . In tissue engineering, researchers use mechanical cues to guide cell behavior and tissue formation.…”

Section: Impact On Drug Development and Tissue Engineeringmentioning

confidence: 99%

“… 50 The tension within the epidermis promotes gene expression through DNA methyltransferase 3A (DNMT3A) nuclear translocation, which is a potential regulator of skin repair. 51 In tissue engineering, researchers use mechanical cues to guide cell behavior and tissue formation. By understanding mechanoregulation, scientists can design better scaffolds and culture conditions for growing tissues and organs in the laboratory.…”

Section: Impact On Drug Development and Tissue Engineeringmentioning

confidence: 99%

The Plasma Membrane and Mechanoregulation in Cells

Mukhopadhyay,

Mandal,

Chakraborty

et al. 2024

ACS Omega

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Cells inhabit a mechanical microenvironment that they continuously sense and adapt to. The plasma membrane (PM), serving as the boundary of the cell, plays a pivotal role in this process of adaptation. In this Review, we begin by examining well-studied processes where mechanoregulation proves significant. Specifically, we highlight examples from the immune system and stem cells, besides discussing processes involving fibroblasts and other cell types. Subsequently, we discuss the common molecular players that facilitate the sensing of the mechanical signal and transform it into a chemical response covering integrins YAP/TAZ and Piezo. We then review how this understanding of molecular elements is leveraged in drug discovery and tissue engineering alongside a discussion of the methodologies used to measure mechanical properties. Focusing on the processes of endocytosis, we discuss how cells may respond to altered membrane mechanics using endo- and exocytosis. Through the process of depleting/adding the membrane area, these could also impact membrane mechanics. We compare pathways from studies illustrating the involvement of endocytosis in mechanoregulation, including clathrin-mediated endocytosis (CME) and the CLIC/GEEC (CG) pathway as central examples. Lastly, we review studies on cell–cell fusion during myogenesis, the mechanical integrity of muscle fibers, and the reported and anticipated roles of various molecular players and processes like endocytosis, thereby emphasizing the significance of mechanoregulation at the PM.

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Initiation of wound healing is regulated by the convergence of mechanical and epigenetic cues

Cited by 8 publications

References 68 publications

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Modulation of gene expression in skin wound healing by photobiomodulation therapy: A systematic review in vivo studies

The Plasma Membrane and Mechanoregulation in Cells

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